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Identification
NameBrinzolamide
Accession NumberDB01194  (APRD00475)
TypeSmall Molecule
GroupsApproved
Description

Brinzolamide is a highly specific, non-competitive, reversible carbonic anhydrase inhibitor. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II). Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure. Brinzolamide is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Structure
Thumb
Synonyms
Azopt
Brinzolamide
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Azoptsuspension/ drops10 mg/mLophthalmicAlcon Laboratories, Inc.1998-04-30Not applicableUs
Azoptsuspension1 %ophthalmicAlcon Canada Inc1998-11-11Not applicableCanada
Sandoz Brinzolamidesuspension1 %ophthalmicSandoz Canada IncorporatedNot applicableNot applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
AzargaAlcon Canada Inc
SimbrinzaAlcon Laboratories, Inc.
SaltsNot Available
Categories
UNII9451Z89515
CAS number138890-62-7
WeightAverage: 383.507
Monoisotopic: 383.064332867
Chemical FormulaC12H21N3O5S3
InChI KeyInChIKey=HCRKCZRJWPKOAR-JTQLQIEISA-N
InChI
InChI=1S/C12H21N3O5S3/c1-3-14-10-8-15(5-4-6-20-2)23(18,19)12-9(10)7-11(21-12)22(13,16)17/h7,10,14H,3-6,8H2,1-2H3,(H2,13,16,17)/t10-/m0/s1
IUPAC Name
(4R)-4-(ethylamino)-2-(3-methoxypropyl)-1,1-dioxo-2H,3H,4H-1λ⁶-thieno[3,2-e][1,2]thiazine-6-sulfonamide
SMILES
CCN[[email protected]]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S2)S(N)(=O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as thienothiazines. These are heterocyclic compounds containing a thiophene ring fused to a thiazine. Thiophene is 5-membered ring consisting of four carbon atoms and one sulfur atom. Thiazine is a 6-membered ring consisting of four carbon, one nitrogen and one sulfur atoms.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassThienothiazines
Sub ClassNot Available
Direct ParentThienothiazines
Alternative Parents
Substituents
  • Thienothiazine
  • 2,3,5-trisubstituted thiophene
  • Aralkylamine
  • Ortho-thiazine
  • Heteroaromatic compound
  • Aminosulfonyl compound
  • Thiophene
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonamide
  • Azacycle
  • Secondary amine
  • Ether
  • Secondary aliphatic amine
  • Dialkyl ether
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
PharmacodynamicsUsed in the treatment of glaucoma, brinzolamide inhibits aqueous humor formation and reduces elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Brinzolamide can decrease intraocular pressure by approximately 16-19% in patients with elevated intraocular pressure.
Mechanism of actionBrinzolamide is a highly specific inhibitor of CA-II, which is the main CA isoenzyme involved in the secretion of aqueous humor. Inhibition of CA in the ciliary process of the eye slows the formation of bicarbonate, and reduces sodium and fluid transport. This results in a reduction in the rate of aqueous humor secretion and the intraocular pressure. Brinzolamide is absorbed systemically following topical ocular administration. Since it has a high affinity for CA-II, brinzolamide binds extensively to red blood cells, where CA-II is primarily found. As sufficient CA-II activity remains, adverse effects resulting from the systemic inhibition of CA by brinzolamide are not observed. The metabolite N-desethyl brinzolamide is also formed. This metabolite binds to CA and accumulates in red blood cells as well. In the presence of brinzolamide, the metabolite binds mainly to carbonic anhydrase I (CA-I).
Related Articles
AbsorptionAbsorbed into systemic circulation following topical ocular application
Volume of distributionNot Available
Protein bindingApproximately 60%.
Metabolism

Ophthalmic

Route of eliminationNot Available
Half life111 days
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9765
Blood Brain Barrier+0.8754
Caco-2 permeable-0.7123
P-glycoprotein substrateSubstrate0.8185
P-glycoprotein inhibitor INon-inhibitor0.6795
P-glycoprotein inhibitor IINon-inhibitor0.9245
Renal organic cation transporterNon-inhibitor0.8276
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6431
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8588
Ames testNon AMES toxic0.5982
CarcinogenicityNon-carcinogens0.7712
BiodegradationNot ready biodegradable0.9834
Rat acute toxicity2.4930 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7097
hERG inhibition (predictor II)Non-inhibitor0.5167
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Suspensionophthalmic
Suspensionophthalmic1 %
Suspension/ dropsophthalmic10 mg/mL
Suspension/ dropsophthalmic
Prices
Unit descriptionCostUnit
Azopt 1% Suspension 15ml Bottle163.11USD bottle
Azopt 1% Suspension 10ml Bottle108.83USD bottle
Azopt 1% eye drops8.05USD ml
Azopt 1 % Suspension3.63USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2080223 No2000-11-072011-04-03Canada
US5240923 No1993-08-312010-08-31Us
US5461081 No1993-04-242013-04-24Us
US6316441 No1999-12-072019-12-07Us
US9044484 No2010-10-302030-10-30Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point131 °CNot Available
logP-1.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.713 mg/mLALOGPS
logP-0.65ALOGPS
logP-0.67ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)8.19ChemAxon
pKa (Strongest Basic)6.78ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area118.8 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity87.2 m3·mol-1ChemAxon
Polarizability37.93 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
References
Synthesis Reference

Alessandro Falchi, Ottorino De Lucchi, Andrea Castellin, “PROCESS FOR THE PREPARATION OF BRINZOLAMIDE.” U.S. Patent US20110118461, issued May 19, 2011.

US20110118461
General References
  1. Ermis SS, Ozturk F, Inan UU: Comparing the effects of travoprost and brinzolamide on intraocular pressure after phacoemulsification. Eye (Lond). 2005 Mar;19(3):303-7. [PubMed:15258611 ]
  2. Iester M, Altieri M, Michelson G, Vittone P, Traverso CE, Calabria G: Retinal peripapillary blood flow before and after topical brinzolamide. Ophthalmologica. 2004 Nov-Dec;218(6):390-6. [PubMed:15564757 ]
  3. Kaup M, Plange N, Niegel M, Remky A, Arend O: Effects of brinzolamide on ocular haemodynamics in healthy volunteers. Br J Ophthalmol. 2004 Feb;88(2):257-62. [PubMed:14736787 ]
  4. Iester M: Brinzolamide ophthalmic suspension: a review of its pharmacology and use in the treatment of open angle glaucoma and ocular hypertension. Clin Ophthalmol. 2008 Sep;2(3):517-23. [PubMed:19668749 ]
  5. DeSantis L: Preclinical overview of brinzolamide. Surv Ophthalmol. 2000 Jan;44 Suppl 2:S119-29. [PubMed:10665514 ]
External Links
ATC CodesS01EC04S01EC54
AHFS Codes
  • 52:10.00
PDB Entries
FDA labelDownload (580 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Brinzolamide.
AmphetamineThe serum concentration of Amphetamine can be increased when it is combined with Brinzolamide.
AtazanavirThe serum concentration of Brinzolamide can be increased when it is combined with Atazanavir.
BoceprevirThe serum concentration of Brinzolamide can be increased when it is combined with Boceprevir.
CeritinibThe serum concentration of Brinzolamide can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Brinzolamide can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Brinzolamide can be increased when it is combined with Cobicistat.
DarunavirThe serum concentration of Brinzolamide can be increased when it is combined with Darunavir.
DiclofenamideThe risk or severity of adverse effects can be increased when Diclofenamide is combined with Brinzolamide.
EthoxzolamideThe risk or severity of adverse effects can be increased when Ethoxzolamide is combined with Brinzolamide.
IdelalisibThe serum concentration of Brinzolamide can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Brinzolamide can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Brinzolamide can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Brinzolamide can be increased when it is combined with Ketoconazole.
NefazodoneThe serum concentration of Brinzolamide can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Brinzolamide can be increased when it is combined with Nelfinavir.
PosaconazoleThe serum concentration of Brinzolamide can be increased when it is combined with Posaconazole.
RitonavirThe serum concentration of Brinzolamide can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Brinzolamide can be increased when it is combined with Saquinavir.
TelaprevirThe serum concentration of Brinzolamide can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Brinzolamide can be increased when it is combined with Telithromycin.
VoriconazoleThe serum concentration of Brinzolamide can be increased when it is combined with Voriconazole.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate ex...
Gene Name:
CA2
Uniprot ID:
P00918
Molecular Weight:
29245.895 Da
References
  1. Stams T, Chen Y, Boriack-Sjodin PA, Hurt JD, Liao J, May JA, Dean T, Laipis P, Silverman DN, Christianson DW: Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide: molecular basis of isozyme-drug discrimination. Protein Sci. 1998 Mar;7(3):556-63. [PubMed:9541386 ]
  2. DeSantis L: Preclinical overview of brinzolamide. Surv Ophthalmol. 2000 Jan;44 Suppl 2:S119-29. [PubMed:10665514 ]
  3. Winum JY, Casini A, Mincione F, Starnotti M, Montero JL, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004 Jan 5;14(1):225-9. [PubMed:14684332 ]
  4. Boriack-Sjodin PA, Zeitlin S, Chen HH, Crenshaw L, Gross S, Dantanarayana A, Delgado P, May JA, Dean T, Christianson DW: Structural analysis of inhibitor binding to human carbonic anhydrase II. Protein Sci. 1998 Dec;7(12):2483-9. [PubMed:9865942 ]
  5. Ilies M, Supuran CT, Scozzafava A, Casini A, Mincione F, Menabuoni L, Caproiu MT, Maganu M, Banciu MD: Carbonic anhydrase inhibitors: sulfonamides incorporating furan-, thiophene- and pyrrole-carboxamido groups possess strong topical intraocular pressure lowering properties as aqueous suspensions. Bioorg Med Chem. 2000 Aug;8(8):2145-55. [PubMed:11003159 ]
  6. Iester M: Brinzolamide ophthalmic suspension: a review of its pharmacology and use in the treatment of open angle glaucoma and ocular hypertension. Clin Ophthalmol. 2008 Sep;2(3):517-23. [PubMed:19668749 ]
  7. Vullo D, Franchi M, Gallori E, Antel J, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J Med Chem. 2004 Feb 26;47(5):1272-9. [PubMed:14971907 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
Gene Name:
CA1
Uniprot ID:
P00915
Molecular Weight:
28870.0 Da
References
  1. Winum JY, Casini A, Mincione F, Starnotti M, Montero JL, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-alpha-D-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004 Jan 5;14(1):225-9. [PubMed:14684332 ]
  2. Herkel U, Pfeiffer N: Update on topical carbonic anhydrase inhibitors. Curr Opin Ophthalmol. 2001 Apr;12(2):88-93. [PubMed:11224713 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.
Gene Name:
CA4
Uniprot ID:
P22748
Molecular Weight:
35032.075 Da
References
  1. Vullo D, Franchi M, Gallori E, Antel J, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J Med Chem. 2004 Feb 26;47(5):1272-9. [PubMed:14971907 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Reversible hydration of carbon dioxide. Low activity.
Gene Name:
CA5A
Uniprot ID:
P35218
Molecular Weight:
34750.21 Da
References
  1. Vullo D, Franchi M, Gallori E, Antel J, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. J Med Chem. 2004 Feb 26;47(5):1272-9. [PubMed:14971907 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on July 23, 2016 01:54